Serotonin (5-hydroxy tryptamine; 5HT) is an endogenous biogenic amine with a well defined neurotransmitter function in many tissues of the body including the eye [Zifa and Fillion, Pharmacol. Rev., 44:401-458, 1992; Hoyer et al., Pharmacol. Rev., 46:157-203, 1994; Tobin et al., J. Neurosci., 8:3713-3721, 1988].
5HT can interact with at least seven major 5HT receptors (5HT1-5HT7) and additional subtypes within these families to initiate intracellular biochemical events such as stimulation of second messengers (e.g. cAMP, inositol trisphosphate) eventually leading to the final biological response, for example, tissue contraction or hormone release, etc. [Hoyer et al., supra; Martin et al., Trends Pharmacol. Sci., 19:2-4, 1998]. Receptor subtypes within the 5HT1 family are negatively coupled to adenylyl cyclase (AC) and cause inhibition of cAMP production, while 5HT4, 5HT6, and 5HT7 receptors are positively coupled to AC and thus stimulate cAMP production when activated by 5HT [Martin et al., supra]. The receptors in the 5HT2 family are positively coupled to phospholipase C (PLC) and thus generate inositol phosphates and mobilize intracellular calcium when activated to mediate the effects of 5HT. The 5HT3 receptor is unique in that it couples to an ion channel which gates sodium, potassium, and calcium [Hoyer et al., supra].
The human and animal 5HT7 receptor has only recently been cloned, expressed, and shown to be present in various brain areas and peripheral tissues [Eglen et al., Trend Pharmacol. Sci., 18:104-107, 1997]. Recent studies have shown there to be four splice variants of the 5HT7 receptor [Heidmann et al., J. Neurochem., 68:1372-1381, 1997]. It has been proposed that the 5HT7 receptor may be involved in the pathophysiology of sleep disorders, depression, and other psychiatric disorders [Eglen et al., supra]. In the periphery, stimulation of 5HT7 receptors results in relaxation of blood vessels and hence vasodilation [Eglen et al., supra]. Improving blood flow to the back of the eye, including the retina, the macula, and the optic nerve head is believed to be beneficial in the treatment of a number of retinal diseases, for example, glaucoma, ARMD, and diabetic retinopathy [Chiou, et al., J. Ocular Pharmacol. 9:13-24 (1993)].
Serotonergic nerves innervate the eye [Tobin et al., J. Neurosci., 8:3713-3721, 1988] and 5HT has been found in the aqueous humor of human eyes [Martin et al., Ophthalmol., 95:1221-1226, 1988]. In addition, receptor binding sites for [3H]5HT have been demonstrated and pharmacologically characterized in the iris-ciliary body (ICB) of rabbits [Mallorga and Sugrue, Curr. Eye Res., 6:527-532, 1987 and Chidlow et al., Invest. Ophthalmol. Vis. Sci., 36:2238-2245, 1995]. These 5HT binding sites have been shown to be functionally coupled to second messenger generation in rabbits [Tobin and Osborne, J. Neurochem., 53:686-601, 1989 and Tobin et al., J. Neurosci, supra]. In the human ICB these binding sites are characterized as 5HT1A and 5HT2 receptors [Barnet and Osborne, Exp. Eye Res., 57:209-216, 1993]. In addition, the presence of mRNAs for 5HT1a and 5HT7 receptors in the rabbit ICB have been reported [Chidlow et al., Invest. Ophthalmol. Vis. Sci., supra and Osborne and Chidlow, Ophthalmologica, 210:308-314, 1996]. The precise functions of these receptors in the eye are unknown, especially the 5HT7 subtype(s).
5HT or 5-carboxamidotryptamine (5-CT) topically applied to the rabbit eye raise intraocular pressure in the anterior chamber of the eye [Meyer-Bothling et al., Invest. Ophthalmol. Vis. Sci., 34:3035-3042, 1993]. By contrast, it has been shown that topically applied 5HT lowers IOP [Krootila et al., J. Ocular Pharmacol., 3:279-290, 1987 (intracamerally 5HT raised IOP and caused breakdown of the blood-aqueous barrier)]. In addition, the 5HT uptake inhibitor, fluoxetine (Prozac®), also raises IOP in human subjects upon oral administration [Costagliola et al., Br. J. Ophthalmol., 80:678, 1996] and may cause glaucoma [Ahmad, Ann. Pharmacother., 25:436, 1992]. However, the 5HT receptor subtype(s) involved in the IOP-elevating effects of 5HT, 5-CT and fluoxetine are unknown.
Studies conducted in rabbits with 8-hydroxy DPAT and MKC-242 (5HT1A agonists) have shown these compounds lower IOP [Osborne and Chidlow, Ophthalmologica, 210:308-319, 1996, and EP 0771563-A2]. In addition, 5-methylurapidil (5HT1A agonist) lowered IOP in glaucomatous monkeys [Wang, et al., Curr. Eye Res., 16:679-775, 1997]. Both MKC-242 and 5-methylurapidil are relatively potent α1 receptor antagonists (α1 antagonists are known to lower IOP in rabbits, monkeys, and man). The mechanism of action for lowering IOP by 5-methylurapidil has been attributed to its α1 antagonist activity and not its 5HT1A agonist activity [Wang, et al., Invest. Ophthal. Vis. Sci., 39(Suppl):2236-488, 1998]. U.S. Pat. No. 5,693,654, discloses 5HT1 receptor agonists for lowering IOP. WO92/20333 discloses certain 5HT1A agonists for the treatment of glaucoma.
Methysergide (5HT2 antagonist) lowered IOP in rabbits [Krootila, et al., Esp. Eye Res., supra]. Ketanserin (5HT2A/C antagonist), also with significant α1 antagonist activity, lowers IOP in rabbits and man [Chan, et al., J. Ocular Pharmacol., 1:137-147, 1985 and Costagliola, et al., Ex. Eye Res., 52:507-510, 1991]. Saprogrelate (5HT2A antagonist) lowers IOP in rabbits and in man when dosed topically or orally [Mano, et al., Invest. Ophthal. Vis. Sci., 36(Suppl):3322-309, 1995, and Takenaka, et al., Invest Ophthal. Vis. Sci., 36(Suppl):3390-377, 1995]. EP 522226 and U.S. Pat. No. 5,290,781 disclose the use of ketanserin and its derivatives for treating ocular hypertension. U.S. Pat. Nos. 5,290,781 and 5,106,555 discloses the use of certain 5HT2 antagonists for lowering IOP. U.S. Pat. No. 5,652,272 discloses saprogrelate for reducing IOP. U.S. Pat. No. 5,538,974 discloses opthalmic compositions of certain 5HT2 antagonists for lowering IOP.
U.S. Pat. No. 5,011,846 discloses certain 5HT3 receptor antagonists for treating glaucoma.
WO 97/17345 discloses that particular compounds with 5HT4 serotonergic receptor agonist or antagonist activity are useful for treating psychiatric, gastrointestinal, lower urinary, and cardiovascular disorders. The publication mentions the compounds may also be useful for glaucoma.
As evidenced by the previous discussion, it is not clear which serotonergic receptor activity is responsible for lowering IOP. Moreover, a number of these compounds are known to have activity at other receptors which are known to be involved in lowering IOP. Furthermore, it has not been cleared which receptor(s) might be responsible for increasing blood flow and providing neuroprotection in the eye.